PROJECT SUMMARY Pharmacotherapy development remains a critical objective for reducing health and societal burdens associated with alcohol use disorder (AUD). Developing targeted treatments for specific AUD subgroups is a key aim under the NIAAA medication development strategy. Among those with AUD, cigarette smokers comprise a sizable and critical subgroup with disproportionally high long-term health risks, making it a key priority to advance therapies for concurrent AUD and cigarette smoking. The serotonin (5-hydroxtytryptamine; 5-HT) system is broadly implicated in addictive behaviors, in part reflecting the role of 5-HT in modulating dopamine function. Preclinical studies of 5-HT receptor drugs have shown that targeted modulation of the 5-HT2C receptor (implicated in 5-HT-related inhibition of DA function) alters the consumption and reinstatement of addictive drugs, including alcohol and nicotine. Additionally, preclinical evidence shows that 5-HT2C receptor agonists attenuate behavioral indices of impulsivity. Of the selective 5-HT2C receptor agonists, lorcaserin has superior near-term potential for repurposing as an AUD therapy, having been approved by the Food and Drug Administration for weight management. A recent Phase II clinical trial supported efficacy of lorcaserin for smoking cessation; however, no human trials have examined lorcaserin's effects on alcohol-related outcomes or measures of impulsivity. Human laboratory medication trials offer a time- and cost-effective option for validating preclinical findings prior to larger randomized controlled trials, and for testing candidate treatment mechanisms. This application proposes a human laboratory screening trial to evaluate lorcaserin as a novel candidate therapy for smokers with AUD. The effects of lorcaserin vs. placebo will be evaluated in a double- blind, within-subjects, crossover study with human laboratory endpoints. This study will provide initial human data on the effects of a 5-HT2C receptor agonist in relation to alcohol-related outcomes, informing its potential for further evaluation as a candidate treatment for AUD.